Optimized bexarotene aerosol formulation inhibits major subtypes of lung cancer in mice.

Bexarotene has exhibited inhibitory effects in preclinical models of lung, mammary gland tumorigenesis and in phase I/II trials of non-small cell lung cancer. The major side effects of bexarotene when administered orally were hypertriglyceridemia and hypercholesterolemia. In our previous study we demonstrated that aerosolized bexarotene through nasal inhalation exhibited potent chemopreventive activity in a lung adenoma preclinical model without the hypertriglyceridemia. To facilitate its future clinical translation, we modified the formula of the aerosolized bexarotene with a clinically relevant solvent system. This optimized aerosolized bexarotene formulation was tested in lung squamous cell carcinoma and lung adenocarcinoma. Aerosolized delivery showed significant chemopreventive effect in these models. The new formula did not show visible signs of toxicity and did not increase plasma levels of triglyceride and cholesterol. The distribution of aerosolized bexarotene in mouse lung, which tested by matrix assisted laser desoprtion/ionization imaging mass spectrometry, demonstrated that aerosolized bexarotene was evenly distributed to the mouse lung parenchyma. Bexarotene modulated the microenvironment in vivo by increasing the tumor infiltrating T cell population. RNA sequencing of the lung cancer cell lines suggested multiple pathways that appear to be altered by bexarotene. For the first time, our studies demonstrate a new, clinically relevant aerosolized bexarotene formulation that exhibits preventive efficacy in major subtypes of lung cancer. This approach would be a major advance in preventing lung cancer incidence in persons at high risk of lung cancer e.g., former or present smokers.